The central objective of this project is to understand the role of Vpr in HIV-1 immunopathogenesis and disease progression. The Applicant proposes to evaluate the mechanisms of Vpr-mediated regulation of CD4+ T cell and macrophage responses, and to assess the possibility that Vpr modulates the in vivo immune response to viral infection. Specifically, the research team will: (1) investigate the direct effects of Vpr on antigen presenting cells and T cells in vitro; (2) determine the extent to which Vpr mediates immune dysregulation using an in vitro immunization model; (3) identify the domains of Vpr involved in mediating these immune functions using Vpr mutants. The proposed studies will lead to an understanding of how Vpr modulates basic cellular events in these important immune cell types and how it may regulate immune functions in vitro and in vivo.